EP1167369A1 - Nouveaux derives de thiazolobenzimidazole - Google Patents

Nouveaux derives de thiazolobenzimidazole Download PDF

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Publication number: EP1167369A1
Authority: EP; European Patent Office
Prior art keywords: lower alkyl; methyl; substituted; compound; benzoimidazole
Prior art date: 1999-04-06
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Withdrawn

Application number

EP00915350A

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German (de)

English (en)

Other versions

EP1167369A4 (fr

Inventor

Satoshi Hayashibe

Hirotsune Itahana

Masamichi Okada

Atsuyuki Kohara

Kyoichi Maeno

Kiyoshi Yahiro

Itsuro Shimada

Kazuhito Tanabe

Kenji Negoro

Takashi Kamikubo

Shuichi Sakamoto

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Yamanouchi Pharmaceutical Co Ltd

Original Assignee

Yamanouchi Pharmaceutical Co Ltd

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1999-04-06

Filing date

2000-04-05

Publication date

2002-01-02

2000-04-05 Application filed by Yamanouchi Pharmaceutical Co Ltd filed Critical Yamanouchi Pharmaceutical Co Ltd

2002-01-02 Publication of EP1167369A1 publication Critical patent/EP1167369A1/fr

2003-05-28 Publication of EP1167369A4 publication Critical patent/EP1167369A4/fr

Status Withdrawn legal-status Critical Current

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

This invention relates to novel thiazolobenzoimidazole derivatives or salts thereof.
the compounds of the invention are useful as medicaments, particularly as a metabotropic glutamate receptor ligand.
compositions which comprise the thiazolobenzoimidazole derivatives or salts thereof as an active ingredient and to intermediates for the synthesis of the compounds of the invention.
Glutamic acid acts as a neurotransmitter in the mammalian central nervous system (Mayer M.L. and Westbrook G.L., Prog . Neurobiol ., 28 (1987) 197 - 276). By the recent studies, importance of glutamic acid in the higher order cranial nerve function has been revealed. Glutamic acid is released from the nerve ending and regulates activity of nerve cells or release of a neurotransmitter, via glutamate receptors which are present in the postsynaptic membrane or nerve ending. Based on various pharmacological and physiological studies, glutamate receptors are currently classified roughly into two categories. One of them is ionotropic receptor and the other is metabotropic receptor (Hollmann M and Heinemann S., Annu. Rev. Neurosci., 17 (1994) 31 - 108).
mGluR metabotropic glutamate receptor
mGluR6 does not exist in the brain but exists only on the retina, so that it is considered that each receptor is taking each own deferent physiological role (Nakanishi S., Neuron, 13 (1995) 1031 - 1037).
the objects of the invention is to provide a thiazolobenzoimidazole derivative which has a novel basal skeleton and shows excellent action upon metabotropic glutamate receptors, and salts thereof, and to further provide a medicament which contains the same.
the present inventors have conducted intensive studies and accomplished the invention by finding that a thiazolobenzoimidazole derivative exerts strong action upon metabotropic glutamate receptors and is useful as a medicament.
the invention relates to a thiazolobenzoimidazole derivative represented by the following general formula (I) or a salt thereof and a pharmaceutical composition which uses the compound as an active ingredient.
R 1 in the above general formula (I) is -A 1 -CO-N(R 6 )-R 7 or a salt thereof.
a compound, or a salt thereof selected from 6- ⁇ [(2-methoxyethyl)amino]methyl ⁇ -N-methyl-N-neopentylthiazolo[3,2-a]benzoimidazole-2-carboxamide, N-cyclohexyl-6- ⁇ [(2-methoxyethyl)amino]methyl ⁇ -N-methylthiazolo[3,2-a]benzoimidazole-2-carboxamide, 6- ⁇ [(3-methoxypropyl)amino]methyl ⁇ -N-methyl-N-neopentylthiazolo[3,2-a]benzoimidazole-2-carboxamide, N-cyclohexyl-N-methyl-6-morpholinomethylthiazolo[3,2-a]benzoimidazole-2-carboxamide, methyl N- ⁇ [2-[cyclohexyl(methyl)carbamoyl]thiazolo[3,2-a]benzoimidazol-6-y
a pharmaceutical composition which comprises the aforementioned thiazolobenzoimidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient, preferably a metabotropic glutamate receptor antagonist, more preferably an agent for preventing or treating cerebral infarction, most preferably an agent for treating cerebral infarction acute phase.
the "lower alkyl” is a C 1-6 alkyl, preferably a C 1-5 alkyl such as methyl, ethyl, propyl, isopropyl, t-butyl or neo-pentyl, more preferably a C 1-3 alkyl.
the "lower alkylene” is a group which further has another bond at an optional position of the above lower alkyl, preferably a C 1-3 alkylene.
lower alkenylene is a group which has one or more double bonds at optional positions of the above lower alkylene, preferably a C 2-4 alkenylene.
halo means fluorine, chlorine, bromine or iodine atom.
cycloalkyl means a cycloalkyl having from 3 to 8 carbon atoms, and those which have bridge(s) are also included therein. Preferred is a cycloalkyl having 5 or 6 carbon atoms. These cycloalkyl may be substituted with lower alkyl(s).
hetero ring together with the adjacent nitrogen atom, which may have other hetero atom(s) means a saturated hetero ring of five- or six-membered single ring formed by combining R 6 with R 7 , which may have 1 or 2 hetero atoms of oxygen, sulfur and nitrogen atoms, in addition to the nitrogen atom to which R 6 and R 7 are attached, and also may have 1 or 2 double bonds in the ring, or a condensed saturated hetero ring formed by condensation of these saturated hetero rings with a cycloalkyl, a saturated hetero ring condensed with benzene ring (e.g., tetrahydroquinoline, indoline or the like) or spiro ring.
R 6 with R 7 which may have 1 or 2 hetero atoms of oxygen, sulfur and nitrogen atoms, in addition to the nitrogen atom to which R 6 and R 7 are attached, and also may have 1 or 2 double bonds in the ring, or a condensed saturated hetero ring formed by condensation of these saturated hetero rings with
hetero ring means a saturated hetero ring or a heteroaryl ring.
hetero ring which may have bridge(s) is a hetero ring which has an alkylene or bridge including hetero atom(s), and quinuclidine and the like can be exemplified.
saturated hetero ring means a saturated hetero ring of five- or six-membered single ring having 1 or 2 hetero atoms of oxygen, sulfur and nitrogen atoms as the ring atoms, and its preferred examples include pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine rings or the like.
heteroaryl means a five- or six-membered single ring or condensed ring heteroaryl group having 1 or 2 hetero atoms of oxygen, sulfur and nitrogen atoms, in addition to the nitrogen atom to which R 5 and R 6 are attached, and its preferred examples include pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine and the like. More preferred is a heteroaryl of five-membered single ring having one nitrogen atom as the other ring atom.
the "spiro ring” means a spiro ring composed of a hetero ring or a cycloalkyl, preferably a bicyclic spiro ring composed of a saturated hetero ring and a cycloalkyl.
the substituent of a group which may be substituted or may have a substituent is as follows.
the substituent means a usual substituent of a group to be substituted commonly used in this field, and its examples include a lower alkyl which may be substituted with OH, a halo-lower alkyl, OH, a lower alkyl-O-CO-, a lower alkyl-O-, a -O-lower alkyl-O-, a -O-aralkyl, a lower alkylthio, a -SO 2 -lower alkyl, a halo, cyano, NO 2 , NH 2 , a mono- or di-lower alkyl-amino, a substitutable aralkyl, a substitutable cycloalkyl, a substitutable aryl, an -O-substitutable aryl, an -S-substitutable aryl, an -SO 2 -substitutable aryl, an -NB-SO 2 -substitutable aryl
halo a lower alkyl, a halo-lower alkyl, hydroxy, a hydroxy-lower alkyl, a lower alkyl-O-, oxo, acyl, acyl-O-, COOH, a lower alkyl-O-CO-, a lower alkyl-O-lower alkyl, NO 2 , cyano, NH 2 , a mono-or di-lower alkyl-amino and a substitutable hetero ring.
the number of substituents is not particularly limited, when it can be substituted, but is preferably from 1 to 4.
the "mono- or di-lower alkyl-amino" means an amino group substituted with 1 or 2 of the aforementioned lower alkyl.
substituted silyloxymethyl means a silyloxymethyl group substituted with a lower alkyl or an aryl.
the compound of the invention exists in optical isomer forms (optically active substances, diastereomers and the like).
a compound having amido bond is included in the compound of the invention, so that tautomers based on the amido bond also exist.
These isomers in the isolated or mixed form are included in the invention.
the compound of the invention forms a salt with an acid or a base.
the salt with an acid include acid addition salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like) or with organic salts (e.g., formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, glutamic acid and the like).
inorganic acids e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like
organic salts e.g., formic acid, acetic acid, propionic acid, oxalic acid
the salt with a base examples include salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum and the like, with organic bases such as methylamine, ethylamine, meglumine, ethanolamine and the like, or with basic amino acids such as lysine, arginine, ornithine and the like, as well as an ammonium salt.
the compound of the invention can form hydrates, solvates such as with ethanol and the like and polymorphism.
a pharmacologically acceptable prodrug is included in the compound of the invention.
the group which forms the pharmacologically acceptable prodrug of the compound of the invention include the groups described in Prog. Med ., 5: 2157 - 2161 (1985) and the groups described in "Development of Drugs" vol. 7, Molecular Designing, pp. 163-198, published in 1990 by Hirokawa Shoten.
a prodrug of OH group includes -OCO-lower alkylene which may be substituted-COOR (R represents H or a lower alkyl, the same shall apply hereinafter), -OCO-lower alkenylene which may be substituted-COOR, -OCO-aryl which may be substituted, -OCO-lower alkylene-O-lower alkylene-COOR, an -OCO-COR, -OCO-lower alkyl which may be substituted, -OSO 2 -lower alkylene which may be substituted-COOR, -O-phthalidyl, 5-methyl-1,3-dioxolen-2-on-4-yl-methyloxy and the like.
the compound of the invention has properties which are more suitable for its clinical use, and a compound having excellent water-solubility is also included in the compound of the invention.
the compound (I) of the invention and synthesis intermediates thereof can be produced by the following production methods.
DMF is abbreviation for dimethylformamide
DMSO dimethyl sulfoxide
THF for tetrahydrofuran
TFA for trifluoroacetic acid
DCE 1,2-dichloroethane
Tol for toluene
EtOAc for ethyl acetate
Py for pyridine
TEA triethylamine
R 18 is a lower alkyl group
R 19 is a lower alkyl group or a lower alkyl-O- group
R 1a is R 1 , COOR 17 or hydrogen
R 20 is -O-R 21 or oxo group by integrating two
R 21 is a lower alkyl group
each of X 1 and X 2 is a halo
R 1 to R 5 , R 4a and R 17 are as defined in the foregoing.
the scheme 1, scheme 2, scheme 3 and scheme 4 are the production method of thiazolo[3,2-a]benzoimidazole ring.
(2a) and (6a) are allowed to react with each other in an alcohol solvent such as EtOH or MeOH or in an inert solvent such as THF, DMF, acetone or acetonitrile, in the presence of a base such as NaOH, KOH, NaH, K 2 CO 3 , NaHCO 3 or the like, or under a neutral condition, at room temperature or under a heated condition.
the (3a, 4a) is allowed to react with an acid halide (8) or an acid anhydride or mixed anhydride (7) in the presence of a base such as Py, TEA or NaOAc under an ice-cooled to heated condition, thereby obtaining (5) which is then subjected to the reaction in the presence of a base such as Py or the like in an inert solvent such as DMF or acetonitrile under a heated condition.
a base such as Py, TEA or NaOAc
(2a) and (6b) are allowed to react with each other in the same manner as the case of the scheme 1, thereby obtaining (3b, 4b) which are then subjected to the reaction under an ice-cooling to heating condition in an acid such as concentrated sulfuric acid, trifluoroacetic acid or acetic acid or in a solvent such as Tol or CCl 4 using the aforementioned acid catalyst such as concentrated sulfuric acid or a Lewis acid catalyst such as BF 3 -Et 2 O.
an acid such as concentrated sulfuric acid, trifluoroacetic acid or acetic acid or in a solvent such as Tol or CCl 4
the aforementioned acid catalyst such as concentrated sulfuric acid or a Lewis acid catalyst such as BF 3 -Et 2 O.
the formed (1b) exists in position isomer forms in some cases depending on the substituents (R 3 , R 4 , R 5 ), but it is possible to produce respective position isomers selectively, for example by using the method shown in the schemee 3 and 4. That is, as shown in the scheme 3, (4c) or (4d) can be obtained as respective crystals by allowing (2a) and (6b) to react with each other like the case of the scheme 2 to obtain an equilibrium mixture (3c, 4c, 4d) and then crystallizing it under an appropriate precipitation condition.
(1c) or (1d) position-selectively by allowing (4c) or (4d) to undergo the reaction under an appropriate condition, e.g., at room temperature or under heating in concentrated sulfuric acid.
(1b) can be produced position-selectively, e.g., by allowing the compound (9) produced by the method shown in the scheme 5 to undergo the reaction under an ice-cooling to heating condition using the aforementioned acid catalyst such as concentrated sulfuric acid or a Lewis acid catalyst such as BF 3 -Et 2 O in an acid such as concentrated sulfuric acid, trifluoroacetic acid or acetic acid or in a solvent such as Tol or CCl 4 .
the aforementioned acid catalyst such as concentrated sulfuric acid or a Lewis acid catalyst such as BF 3 -Et 2 O
an acid such as concentrated sulfuric acid, trifluoroacetic acid or acetic acid or in a solvent such as Tol or CCl 4 .
R 35 is R 22 , -OR 17 , -NH-R 26 or hydroxy group
R 22 is -A 2 -R 8
R 23 is a lower alkyl group or alkali metal atom (e.g., Li, Na or the like)
R 24 and R 25 are the same or different lower alkyl or one of them is lower alkyl-O- group
R 26 is R 6 or R 7
X 3 is a halo
R 2 to R 8 , R 17 and A 2 are as defined in the foregoing.
(1e) is metallized using an organic metal reagent (e.g., BuLi, iPr 2 NLi or the like) in an inert solvent (e.g., THF, Et 2 O or the like) at a low temperature, preferably-78°C, and the product is allowed to react with corresponding acid halide (14), ester (15), amide (16), isocyanate (17), carbonic acid ester (18) or carbon dioxide at the same temperature to room temperature.
organic metal reagent e.g., BuLi, iPr 2 NLi or the like
an inert solvent e.g., THF, Et 2 O or the like
the scheme 7 and scheme 8 are usual amidation reactions.
the reaction is carried out by converting a carboxylic acid into an acid chloride using a halogenation agent such as SOCl 2 or (COCl) 2 and then allowing the salt to undergo the reaction at ice-cooling to room temperature, or if necessary under a heating condition, in the presence of a corresponding primary or secondary amine and an organic base such as TEA or Py or an inorganic base such as NaHCO 3 or K 2 CO 3 , in an inert solvent such as DCE, CB 2 Cl 2 , CHCl 3 or 1,4-dioxane or in a two layer system solvent thereof with water, or using a base such as Py itself as the solvent.
a halogenation agent such as SOCl 2 or (COCl) 2
an organic base such as TEA or Py
an inorganic base such as NaHCO 3 or K 2 CO 3
an inert solvent such as DCE, CB 2 Cl 2
a usually used method can also be used, such as a method in which the carboxylic acid is made into a mixed acid anhydride and then allowed to react with an amine, a method in which POCl 3 is used as a condensing agent in Py solvent or a method in which amidation is directly carried out in the presence of an appropriate condensing agent such as diphenylphosphorylazide (to be referred to as DPPA hereinafter) or 1,1'-carbonylbis-1H-imidazole (to be referred to as CDI hereinafter).
DPPA diphenylphosphorylazide
CDI 1,1'-carbonylbis-1H-imidazole
the scheme 9 is a method for the synthesis of a carbamic acid ester, and amine (1i) is allowed to react with (21) or (22) under ice-cooling to heating in an inert solvent (e.g. DCE, CH 2 Cl 2 , CHCl 3 , THF, DMF or the like) in the presence of a base (e.g., TEA, 4-(N,N-dimethylamino)pyridine (DMAP), Py or the like), or under a neutral condition.
an inert solvent e.g. DCE, CH 2 Cl 2 , CHCl 3 , THF, DMF or the like
a base e.g., TEA, 4-(N,N-dimethylamino)pyridine (DMAP), Py or the like
the scheme 10 is a usual esterification reaction.
the reaction is carried out with a corresponding alcohol (23), or using (23) itself as the solvent, in an inert solvent (e.g., Tol, THF or the like) in the presence of a catalyst such as concentrated sulfuric acid, concentrated hydrochloric acid, p-toluenesulfonic acid or the like at room temperature to heating condition, while dehydrating using a molecular sieve or Dean-Stark dehydration apparatus as occasion demands, or the carboxylic acid (1g) is allowed to react with a corresponding alkyl halide under an ice-cooling to heating condition in an inert solvent (e.g., DMF, THF or the like) in the presence of a base (e.g., NaH, K 2 CO 3 or the like).
an inert solvent e.g., DMF, THF or the like
a base e.g., NaH, K 2 CO 3 or the like
SOCl 2 is added dropwise to an alcohol (23) solution of (1g) under ice-cooling, and the reaction is further carried out under a heating condition as occasion demands, or (1g) is converted into an acid chloride or active ester and then allowed to react with (23).
the scheme 11 is Curtius rearrangement.
the reaction is carried out by converting the carboxylic acid (1g) into an acid azide under a usual acid azide producing condition, illustratively a method in which the carboxylic acid is allowed to react with an azide forming agent such as DPPA or the like at ice-cooling to room temperature in an inert solvent (e.g., DMF or the like) or a method in which the carboxylic acid is converted into an acid halide, active ester or acid anhydride and then allowed to react with an azide forming agent (e.g., NaN 3 or the like), and then the reaction is carried out under a heating condition in the presence of a corresponding alcohol (24) in an inert solvent (e.g., DMF, Tol, THF or the like), or using the reacting alcohol (24) itself as the solvent.
an azide forming agent e.g., DPPA or the like
an azide forming agent e.g., Na
R 27 is hydrogen or a lower alkyl group which may have a substituent, and R 6 , R 7 , R 17 and A 1 are as defined in the foregoing.
the schemes 12 to 14 are reduction reactions by a metal hydride.
R 17 in the scheme 12 is hydrogen, the carboxylic acid (1i) is allowed to undergo the reaction under cooling to heating condition using BH 3 or a complex thereof in an inert solvent (e.g., THF, Et 2 O or the like), or (1i) is converted into an acid halide using a halogenation agent (e.g., SOCl 2 , (COCl) 2 or the like) or into an active ester using a condensing agent (e.g., CDI or the like), and then allowed to undergo the reaction under ice-cooling or, as occasion demands, under a heating condition, in the aforementioned inert solvent or a mixed solvent thereof with water using a reducing agent (e.g., NaBH 4 , LiBH 4 , LiAlH 4 , (iBu) 2 AlH or the like).
a reducing agent e.g., NaBH 4 , LiBH 4 , LiAlH
R 17 in the scheme 12 is a lower alkyl group
the ester (1i) is allowed to undergo the reaction in an inert solvent (e.g., THF, Et 2 O or the like) or a mixed solvent thereof with EtOH, MeOH or the like, using the aforementioned reducing agent at -78°C to room temperature, or under a heating condition as occasion demands.
reaction of the amide (1h) is carried out using a reducing agent such as a complex (e.g., LiAlH 4 , (iBu) 2 AlH or BH 3 or BH 3 -Me 2 S or the like), in the aforementioned inert solvent under an ice-cooling to heating condition.
a complex e.g., LiAlH 4 , (iBu) 2 AlH or BH 3 or BH 3 -Me 2 S or the like
reaction of the aldehyde (1o) is carried out using a reducing agent (e.g., LiBH 4 , NaBH 4 , LiAlH 4 , (iBu) 2 AlH or the like) at -78°C to room temperature in the aforementioned inert solvent, an alcohol or water.
a reducing agent e.g., LiBH 4 , NaBH 4 , LiAlH 4 , (iBu) 2 AlH or the like
the schemes 15 to 18 are alkali or acid hydrolysis. That is, the reaction is carried out at room temperature or under a heating condition in a solvent such as MeOH, EtOH, THF, 1,4-dioxane, EtOAc or water or in a mixed solvent thereof, using NaOH, KOH, K 2 CO 3 or the like in the case of alkali hydrolysis or hydrazine, methyl amine or the like in the case of the scheme 18, or using sulfuric acid, hydrochloric acid, nitric acid, TFA or the like in the case of acid hydrolysis.
a solvent such as MeOH, EtOH, THF, 1,4-dioxane, EtOAc or water or in a mixed solvent thereof, using NaOH, KOH, K 2 CO 3 or the like in the case of alkali hydrolysis or hydrazine, methyl amine or the like in the case of the scheme 18, or using sulfuric acid, hydrochloric acid, nitric acid, TFA or the like in the case of
R 28 is -A 2 -R 9
X 5 is a halo or sulfonyloxy group
X 6 is a halo
R 9 , A 2 and A 1 are as defined in the foregoing, with the proviso that A 1 does not have hydroxy group in the schemes 19 and 20.
the scheme 19 is halogenation or sulfonyloxy formation of alcohol and subsequent O-alkylation reaction.
X 5 in the scheme 19 is a halo
(1m) of the steps of from (1m) to (1t) is allowed to undergo the reaction under an ice-cooling to heating condition using a halogenation agent (e.g., SOCl 2 , (COCl) 2 or the like) in an inert solvent (e.g., THF, 1,4-dioxane, CH 2 Cl 2 , CCl 4 or the like), or using the halogenation agent itself as the solvent.
a halogenation agent e.g., SOCl 2 , (COCl) 2 or the like
an inert solvent e.g., THF, 1,4-dioxane, CH 2 Cl 2 , CCl 4 or the like
X 5 is sulfonyloxy
the reaction is carried out in the aforementioned inert solvent under an ice-cooling to room temperature condition in the presence of a base (e.g., TEA, Py or the like), using a sulfonyl forming agent (e.g., methanesulfonyl chloride, p-toluenesulfonyl chloride or the like).
a base e.g., TEA, Py or the like
a sulfonyl forming agent e.g., methanesulfonyl chloride, p-toluenesulfonyl chloride or the like.
(1v) can be converted into (1w) by carrying out the reaction under a heating condition using a halogenation agent (e.g., N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS) or the like), in an inert solvent (e.g., CCl 4 , CHCl 3 or the like) in the presence of a catalytically effective amount of a radical initiator (e.g., 2,2'-azobisisobutyronitrile (AIBN), dibenzoyl peroxide or the like).
a halogenation agent e.g., N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS) or the like
NBS N-bromosuccinimide
NCS N-chlorosuccinimide
an inert solvent e.g., CCl 4 , CHCl 3 or the like
the reaction with an alcohol (25) is carried out under an ice-cooling to heating condition in an inert solvent (e.g., DMF, DMSO, THF, acetone, acetonitrile or the like) using a base (e.g., NaH, KOH, NaOH, K 2 CO 3 or the like).
an inert solvent e.g., DMF, DMSO, THF, acetone, acetonitrile or the like
a base e.g., NaH, KOH, NaOH, K 2 CO 3 or the like
R 29 is a lower alkyl group
X 6 is a halo or sulfonyloxy
R 6 , R 7 , R 27 , X 5 , and A 1 are as defined in the foregoing.
the scheme 21 is N-alkylation reaction of amine, and the compound (1t) is allowed to react with an amine (19) under an ice-cooling to heating condition in an inert solvent (e.g., DMF, acetonitrile, acetone, CH 2 Cl 2 or the like) in the presence of a base (e.g., K 2 CO 3 , NaHCO 3 , TEA or the like), or using an excess amount of the amine (19) to be reacted.
an inert solvent e.g., DMF, acetonitrile, acetone, CH 2 Cl 2 or the like
a base e.g., K 2 CO 3 , NaHCO 3 , TEA or the like
the scheme 22 is N-alkylation reaction of amide, and the compound (1x) is allowed to react with an alkylating agent (e.g., an alkyl halide, sulfonic acid alkyl ester (26) or the like) under an ice-cooling to heating condition in the presence of a base (e.g., NaH, K 2 CO 3 or the like).
an alkylating agent e.g., an alkyl halide, sulfonic acid alkyl ester (26) or the like
a base e.g., NaH, K 2 CO 3 or the like
the scheme 23 is Mitsunobu reaction in which an alcohol (1m) is allowed to react with an imide (27) under an ice-cooling to heating condition in an inert solvent (e.g., THF or the like) in the presence of an azodicarboxylic acid ester and Ph 3 P.
the scheme 24 is reductive amination reaction in which an aldehyde or ketone (1o) is allowed to react with an amine (19) under an ice-cooling to heating condition in a solvent (e.g., DCE, CH 2 Cl 2 , THF, MeOH or EtOH or the like), using a reducing agent (e.g., NaB(Ac) 3 H, NaB(CN)H 3 or NaBH 4 or the like) in the presence of an acid catalyst (e.g., acetic acid, hydrochloric acid or the like) or a Lewis acid catalyst (e.g., Ti(OiPr) 4 or the like).
a solvent e.g., DCE, CH 2 Cl 2 , THF, MeOH or EtOH or the like
a reducing agent e.g., NaB(Ac) 3 H, NaB(CN)H 3 or NaBH 4 or the like
an acid catalyst e.g., acetic acid, hydrochloric acid or
the reaction can also be carried out under a usual catalytic reduction condition, instead of using the aforementioned reducing agent, illustratively in an atmosphere of hydrogen using a metal catalyst (e.g., Pd or the like).
the scheme 26 is a Michael addition reaction in which an amine (1i) is allowed to react with an ⁇ , ⁇ -conjugated carbonyl (28) at room temperature or under a heating condition in a solvent (e.g., EtOH, MeOH or the like) in the presence of a base (e.g., NaOEt or the like), or under an acidic condition such as of acetic acid or under a neutral condition.
a solvent e.g., EtOH, MeOH or the like
a base e.g., NaOEt or the like
the azide compound (lc') can be produced by allowing (1t) to react with an azide forming agent (e.g., NaN 3 or the like).
the scheme 27 is a nitration reaction.
the reaction is carried out using nitric acid-sulfuric acid, nitric acid-acetic acid or nitric acid-acetic anhydride at ice-cooling to room temperature, or under a heating condition as occasion demands.
a nitrating agent e.g., NO 2 -BF 4 or the like
an inert solvent e.g., Tol, acetonitrile, THF, sulfolane or the like
R 31 is nitro group or azido group, and A 1 is as defined in the foregoing.
the scheme 28 is a reduction reaction of nitro group or azido group.
the reaction is effected by carrying out catalytic reduction in an atmosphere of hydrogen or in the presence of a hydrogen donor such as ammonium formate, using a metal catalyst (e.g., Pd, Pt or the like), using Fe, SnCl 2 or the like in the presence of an acid such as acetic acid or hydrochloric acid when R 31 is nitro group or using a reducing agent (e.g., sodium hydrosulfite or the like) in a mixed solvent of water with MeOH, THF or the like under room temperature to heating condition.
a hydrogen donor such as ammonium formate
a metal catalyst e.g., Pd, Pt or the like
Fe SnCl 2 or the like
an acid such as acetic acid or hydrochloric acid
a reducing agent e.g., sodium hydrosulfite or the like
the scheme 29 is Sandmeyer reaction, and the reaction is carried out by allowing the aniline compound (lh') to react with a nitrite such as NaNO 2 in an aqueous solution such as of hydrochloric acid or sulfuric acid at an ice-cooling to room temperature, thereby forming a diazonium salt which is subsequently neutralized and then allowed to react with KCN, NaCN or a mixture thereof with CuCN in a mixed solvent of water with an organic solvent such as Tol at a ice-cooling to room temperature or under a heating condition as occasion demands.
a nitrite such as NaNO 2
an aqueous solution such as of hydrochloric acid or sulfuric acid
the schemes 30 and 31 are halogenation reaction.
the reaction is carried out using bromine, an ammonium complex thereof or chlorine as a halogenation agent, by allowing the starting compound to react with bromine in a solvent (e.g., CCl 4 , THF, MeOH or the like) at an ice-cooling to heating temperature, if necessary by adding concentrated hydrochloric acid.
a solvent e.g., CCl 4 , THF, MeOH or the like
R 27 and A 1 are as defined in the foregoing.
the scheme 32 is an alcohol oxidation reaction.
the reaction is carried out at a temperature of from -78°C to room temperature in an inert solvent such as CH 2 Cl 2 using DMSO, (COCl) 2 or TEA, or under an ice-cooling to room temperature condition in DMSO solvent using SO 3 -Py.
an inert solvent such as CH 2 Cl 2 using DMSO, (COCl) 2 or TEA
SO 3 -Py SO 3 -Py.
it can be produced by a usual oxidation reaction, illustratively, by oxidation with chromic acid, permanganic acid or the like.
R 31 is an allyl group
X 7 is a halo or trifluoromethanesulfonyloxy group
R 6 and R 1 are as defined in the foregoing.
the scheme 33 is allylation reaction of amine, and the reaction is carried out by allowing the amine compound (1i) to react with an allyl halide or allyl trifurate (30) in an inert solvent such as DMF or without solvent in the presence or absence of a base such as K 2 CO 3 , or in the same manner in the presence of a catalyst such as Pd or Cu when the allyl trifurate has low activity.
R 32 to R 34 may be the same or different from one another and each represents a lower alkyl group or phenyl group, and A 1 is as defined in the foregoing.
the scheme 34 is a silylation reaction of alcohol, in which an alcohol (1m) is allowed to react with a silylation agent such as silane chloride (31) in an inert solvent (e.g., DCE, CH 2 Cl 2 , CHCl 3 or the like) in the presence of a base (e.g., imidazole, Et 3 N, N,N-dimethyl-4-aminopyridine (DMAP), Py or the like), under ice-cooling to heating condition.
a silylation agent such as silane chloride (31)
an inert solvent e.g., DCE, CH 2 Cl 2 , CHCl 3 or the like
a base e.g., imidazole, Et 3 N, N,N-dimethyl-4-aminopyridine (DMAP), Py or the like
R 32 to R 34 and A 1 are as defined in the foregoing.
the scheme 35 is a desilylation reaction of silyl ether, in which (1n') is allowed to react with a desilylation agent (e.g., KF, tetrabutylammonium fluoride (TBAF) or the like) at room temperature or under a heating condition in a solvent (e.g., THF, methanol or the like).
a desilylation agent e.g., KF, tetrabutylammonium fluoride (TBAF) or the like
a solvent e.g., THF, methanol or the like.
reaction schemes described in the above production methods are shown by typical structures, so that they are not restricted by the substituents of the formulae and can be broadly applied to a case in which a compound of the invention has similar substituents or a case in which a reaction substrate and a reactant have opposite relation.
the compound of the invention produced in this manner is isolated and purified in its free form or as a salt thereof.
the isolation and purification are carried out by employing usual chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization and various types of chromatography.
optical isomers can be separated into stereochemically pure isomers by selecting an appropriate material or by a method for the optical resolution of racemic compounds (e.g., a method in which they are converted into diastereomer salts with a general optically active base and then subjected to optical resolution).
a pharmaceutical preparation which contains one or more of the compounds of the invention or salts thereof as an active ingredient is prepared using carriers, fillers and other additives generally used in the preparation of medicaments.
the carriers and fillers for pharmaceutical preparation use may be either solid or liquid, and their examples include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cacao butter, ethylene glycol and other generally used substances.
It may be administered either by oral administration through tablets, pills, capsules, granules, powders, solutions or the like, or by parenteral administration through injections such as for intravenous injection, intramuscular injection or the like, suppositories, percutaneous preparations and the like.
Its dose is optionally decided by taking into consideration conditions of each case such as symptoms, age, sex and the like of the patient to be treated, but, usually, it is orally administered within the range of from 0.1 to 1,000 mg, preferably from 0.5 to 200 mg, per day per adult by dividing the daily dose into 1 to several doses per day or intravenously injected within the range of from 0.1 to 500 mg per day per adult by dividing the daily dose into 1 to several doses per day or continuously within the range of from 1 to 24 hours per day.
a smaller dose than the above range may be sufficient enough in some cases.
the solid composition for use in the oral administration according to the invention is used in the forms of tablets, powders, granules and the like.
one or more active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, metasilicate or magnesium aluminate.
the composition may contain other additives than the inert diluent, which include a lubricant such as magnesium stearate, a disintegrating agent such as calcium cellulose glycolate, a stabilizing agent such as lactose and a solubilization assisting agent such as glutamic acid or aspartic acid.
a lubricant such as magnesium stearate
a disintegrating agent such as calcium cellulose glycolate
a stabilizing agent such as lactose
a solubilization assisting agent such as glutamic acid or aspartic acid.
tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose or hydroxypropylmethylcellulose phthalate.
the liquid composition for oral administration use includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like and contains a generally used inert diluent such as purified water or ethanol.
this composition may also contain auxiliary agents such as a moistening agent and a suspending agent, as well as a sweetener, a flavor, an aromatic and an antiseptic.
the injections for parenteral administration use include aseptic aqueous or non-aqueous solutions, suspensions and emulsions.
examples of the diluent for use in the aqueous solutions and suspensions include distilled water for injection use and physiological saline.
examples of the diluent for use in the non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, plant oil (e.g., olive oil or the like), alcohol (e.g., ethanol or the like) and polysorbate 80.
Such a composition may further contain auxiliary agents such as an antiseptic, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizing agent (e.g., lactose) and a solubilization assisting agent (e.g., glutamic acid or aspartic acid).
auxiliary agents such as an antiseptic, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizing agent (e.g., lactose) and a solubilization assisting agent (e.g., glutamic acid or aspartic acid).
auxiliary agents such as an antiseptic, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizing agent (e.g., lactose) and a solubilization assisting agent (e.g., glutamic acid or aspartic acid).
These compositions are sterilized by, e.g., filtration through
CDI (65 g) was added to THF (500 ml) suspension of the compound of Reference Example 4 (50 g) and stirred at 60°C for 2 hours. After cooling the reaction solution to -20°C, aqueous solution (200 ml) of NaBH 4 (30 g) was gradually added thereto, and the mixture was stirred under ice-cooling for 2 hours. At the same temperature, this was mixed with concentrated hydrochloric acid (200 ml) and water (200 ml) and further stirred overnight at room temperature. The reaction solution was neutralized with 20% NaOH aqueous solution, and the thus precipitated crystals were collected by filtration to obtain the title compound (25 g).
Example 50 The compound of Example 50 (12.5 g) was dissolved in a mixed solvent of THF (230 ml)/MeOH (120 ml), and the solution was mixed with aqueous solution (100 ml) of Na 2 S 2 O 4 (30.4 g) and heated under reflux for 3 hours. After cooling, the reaction solution was mixed with concentrated hydrochloric acid (30 ml) and again heated under reflux for 1 hour. The reaction solution was concentrated under a reduced pressure, diluted with water and then neutralized with NaOH.
silica gel was used as the filler of the column chromatography.
Example 3 The compound of Example 3 (12.3 g) was dissolved in concentrated sulfuric acid, and this was mixed with fuming nitric acid (1.95 ml) under ice-cooling and then stirred at room temperature for 30 minutes. The reaction solution was poured into ice water and neutralized by adding saturated NH 3 aqueous solution, and then the thus formed precipitate was collected by filtration. The thus collected crude crystals were washed with hot MeOH to obtain the title compound (12.7 g).
the compound of Reference Example 6 (5 g) was mixed with 1 M HCl aqueous solution (50 ml) and stirred, and then water was evaporated under a reduced pressure. The residue was suspended in DMF (50 ml) and mixed with 1-hydroxybenzotriazole (3.6 g) and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (WSC HCl) (11.6 g) at room temperature, and then the mixture was stirred at the same temperature for 2 hours.
1-hydroxybenzotriazole 3.6 g
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (11.6 g)
MeOH (5 ml) solution of the compound of Example 69 (42 mg) was mixed with 1 M NaOH aqueous solution, and the mixture was stirred at room temperature for 1 hour. After evaporation of MeOH under a reduced pressure, the residue was separated between water and EtOAc, and the organic layer was washed with water and saturated brine. After drying with Na 2 SO 4 , the solvent was evaporated under a reduced pressure and the resulting residue was washed with a small amount of EtOAc to obtain the title compound (23 mg).
Example 64 Under ice-cooling, the compound of Example 64 (0.99 g) was added to SOCl 2 (5 ml) and stirred at the same temperature for 2 hours, and then SOCl 2 was evaporated under a reduced pressure to obtain 6-chloromethyl-N-methyl-N-neopentylthiazolo[3,2-a]benzoimidazole-2-carboxamide hydrochloride (1.15 g). The thus obtained compound (200 mg) was dissolved in DMF (10 ml), and the solution was mixed with 2-methoxyethylamine (390 mg) and K 2 CO 3 (1.0 g) and stirred at room temperature for 3 days.
reaction solution was poured into water, extracted with EtOAc, washed with water and saturated brine and dried with MgSO 4 , and then the solvent was evaporated under a reduced pressure.
Example 87 The compound of Example 87 (0.11 g) was dissolved in MeOH (5 ml), mixed with 1 M NaOH aqueous solution (0.52 ml) and stirred at room temperature for 6 hours. The reaction solution was neutralized with 1 M HCl, the solvent was evaporated under a reduced pressure and then the residue was purified by a column chromatography. The resulting residue was dissolved in MeOH, mixed with 4 M HCl EtOAc solution and stirred, and then the solvent was evaporated under a reduced pressure to obtain crude crystals. The crude crystals were washed with EtOAc and dried to obtain the title compound (92 mg).
the compound of Reference Example 13 (376 mg) was dissolved in THF (30 ml) and then, in an atmosphere of argon and at -78°C, this was mixed with 1.6 M n-BuLi Hex solution (1.5 ml) and stirred at the same temperature for 30 minutes. Next, this was mixed with cyclohexanecarbonyl chloride (40 ml) and further stirred for 30 minutes. After completion of the reaction, this was mixed with water to increase temperature, extracted with EtOAc, washed with 1 M NaOH aqueous solution, water and saturated brine and then dried with anhydrous Na 2 SO 4 .
An evaluation system which uses mGluR1 expression cells is known as a method for confirming effects of compounds that act upon mGluR1, but this evaluation system is complex due, e.g., to the use of cells.
PI phosphatidylinositol
the tritium-labeled compound used in the binding test was produced by carrying out selective N-methylation of the amide of 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzoimidazole-2-carboxamide which had been synthesized from 3-methylthiazolo[3,2-a]benzoimidazole-2-carboxylic acid and cyclohexylamine in accordance with Production Example 1 described in WO 99/44639, in DMF using NaH and [ 3 H]-methyl iodide (CT 3 I). Specific activity; 83 Ci/mmol (Amersham)
Rats (Wistar, males, 9 to 12 weeks of age) were decapitated to excise cerebella. After weight measurement, they were homogenized in 7 to 10 volumes of 0.32 M sucrose solution. After 15 minutes of centrifugation at 900 x g, the supernatant was preserved in a container (in ice). The precipitate was again homogenized in 0.32 M sucrose solution of the same volume of the first time and centrifuged at 900 x g for 15 minutes. The supernatant obtained this time was combined with the previously obtained supernatant and centrifuged at 15,000 x g for 20 minutes.
the precipitate was homogenized in 5 mM Tris-HCl, pH 7.4, and centrifuged at 15,000 x g for 15 minutes. This step was repeated again.
the precipitate was homogenized in 50 mM Tris-HCl, pH 7.4, and centrifuged at 15,000 x g for 15 minutes.
the precipitate was homogenized in an appropriate amount of 50 mM Tris-HCl, pH 7.4, subdivided into small portions and then preserved at -80°C.
the binding test was carried out by the following modified method of Thomsen et al.
As the assay buffer 50 mM Tris-HCl, 2.5 mM CaCl 2 , pH 7.4, was used.
a test compound and about 0.1 mg of the rat cerebellum P2 membrane fraction were suspended in the buffer to a total volume of 200 ⁇ l, dispensed into each of test tubes or wells of a 96 well microplate and then incubated at room temperature (about 25°C) for 45 minutes.
Completion of the incubation was effected by a filtration method using Whatman GF/B filter. Quantity of the radioactivity was measured using a liquid scintillation counter. The K D value in the saturation test was 47 nM, and B max was 3.9 pmol/mg protein.
the compound of the invention was dissolved in physiological saline and adjusted to 6 mg/3 ml.
the compound of the invention having strong affinity for mGluR1 clearly showed the effect to reduce cerebral infarction volume in an animal model of cerebral infarction having an infarction area caused by local ischemia. Based on these results, it was confirmed that the compound of the invention having strong affinity for mGluRl, particularly mGluR1 antagonism, is a drug useful for the treatment of cerebral infarction, particularly acute phase cerebral infarction.
a novel thiazolobenzoimidazole derivative which acts upon mGluR1 is provided.
the compound of the invention is useful as an agent for the prevention and treatment of diseases, preferably cerebral infarction, in which mGluR1 is considered to be taking a role.

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EP00915350A 1999-04-06 2000-04-05 Nouveaux derives de thiazolobenzimidazole Withdrawn EP1167369A4 (fr)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
JP9906299		1999-04-06
JP9906299		1999-04-06
PCT/JP2000/002199 WO2000059913A1 (fr)	1999-04-06	2000-04-05	Nouveaux derives de thiazolobenzimidazole

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EP1167369A1 true EP1167369A1 (fr)	2002-01-02
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US (1)	US6642264B1 (fr)
EP (1)	EP1167369A4 (fr)
KR (1)	KR20010006951A (fr)
CN (1)	CN1120842C (fr)
AR (1)	AR023381A1 (fr)
AU (2)	AU2241400A (fr)
CA (1)	CA2365419A1 (fr)
MX (1)	MXPA00003390A (fr)
PL (1)	PL339443A1 (fr)
WO (1)	WO2000059913A1 (fr)

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US7250429B2 (en)	2002-03-20	2007-07-31	Astellas Pharma Inc.	Aminomethyl-substituted thiazolobenzimidazole compounds
WO2007148113A1 (fr) *	2006-06-23	2007-12-27	Merz Pharma Gmbh & Co. Kgaa	Modulateurs du récepteur métabotropique du glutamate
WO2009087218A1 (fr) *	2008-01-10	2009-07-16	Glaxo Group Limited	Thiazoltriazoles et thiazolimidazoles comme antagonistes du récepteur mglur5
EP1485082A4 (fr) *	2002-02-19	2009-12-30	Xenoport Inc	Procede de synthese de promedicaments a partir de derives de 1-acyl-alkyl et compositions correspondantes
EP2298778A4 (fr) *	2008-06-12	2011-10-05	Daiichi Sankyo Co Ltd	Dérivé d imidazothiazole ayant une structure cyclique de 4,7-diazaspiroý2.5¨octane
CN108017659A (zh) *	2017-12-04	2018-05-11	沈阳药科大学	苯并咪唑并噻唑甲酰胺类化合物及其应用

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EP2298778A4 (fr) *	2008-06-12	2011-10-05	Daiichi Sankyo Co Ltd	Dérivé d imidazothiazole ayant une structure cyclique de 4,7-diazaspiroý2.5¨octane
CN108017659A (zh) *	2017-12-04	2018-05-11	沈阳药科大学	苯并咪唑并噻唑甲酰胺类化合物及其应用

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AU3670000A (en)	2000-10-23
PL339443A1 (en)	2000-10-09
CA2365419A1 (fr)	2000-10-12
AU2241400A (en)	2000-10-12
EP1167369A4 (fr)	2003-05-28
WO2000059913A1 (fr)	2000-10-12
KR20010006951A (ko)	2001-01-26
CN1271731A (zh)	2000-11-01
MXPA00003390A (es)	2005-09-15
AR023381A1 (es)	2002-09-04
US6642264B1 (en)	2003-11-04
CN1120842C (zh)	2003-09-10

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